Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.

TitleChromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.
Publication TypeJournal Article
Year of Publication2021
AuthorsL Wang, E Wang, Prado J Balcazar, Z Wu, K Xiang, Y Wang, Q Huang, M Negrete, K-Y Chen, W Li, Y Fu, A Dohlman, R Mines, L Zhang, Y Kobayashi, T Chen, G Shi, JP Shen, S Kopetz, PR Tata, V Moreno, C Gersbach, G Crawford, D Hsu, E Huang, P Bu, and X Shen
JournalAdvanced Science (Weinheim, Baden Wurttemberg, Germany)
Volume8
Start Pagee2004673
Issue19
Date Published10/2021
Abstract

Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC-related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1-remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment-induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.

DOI10.1002/advs.202004673
Short TitleAdvanced Science (Weinheim, Baden Wurttemberg, Germany)